Protective effect and mechanism of Ershiwuwei Zhenzhu Pills on cerebral apoplexy rats / 中国中药杂志

To study the protective effect of Ershiwuwei Zhenzhu Pills on ischemic stroke rats. Ninety 4-weeks-old SPF male SD rats were randomly divided into 6 groups(n=15):sham operation group, model group, nimodipine group(12 mg·kg~(-1)), Ershiwuwei Zhenzhu Pills high-dose group(400 mg·kg~(-1)), Ershiwuwei Zhenzhu Pills medium-dose group(200 mg·kg~(-1)), Ershiwuwei Zhenzhu Pills low-dose group(100 mg·kg~(-1)).The permanent middle cerebral artery occlusion model(PMCAO) was established in the model group, nimodipine group, and Ershiwuwei Zhenzhu Pills groups by the improved thread plug method, while the sham operation group did not insert the thread plug.Nimodipine group and Ershiwuwei Zhenzhu Pills groups were given intragastric administration once a day for 24 days before the modeling operation, and once 1 hour before the modeling operation, while sham operation group and model group were given equal volumes of distilled water.The neuroethology of the surviving rats was measured; The volume of cerebral infarction in rats was measured by TTC method; The histopathology of rat brain was observed by HE method; The expression levels of tumor necrosis factor α(TNF-α),interleukin-1β(IL-1β),interleukin-6(IL-6),malondialdehyde(MDA),superoxide dismutase(SOD) and catalase(CAT) in serum were detected by ELISA;The mRNA expressions of Notch 1,Jagged 1,Hes 1 and Bcl-2 in rat brain were detected by RT-PCR;Western blot was used to detect the expression levels of caspase-3 protein in rat brain; the expression levels of vascular endothelial growth factor(VEGF) and CD34 positive cells in rat brain were detected by immunofluorescence.The low, medium and high dose groups of Ershiwuwei Zhenzhu Pills and nimodipine group could significantly reduce the neurobehavioral score and cerebral infarction volume of rats with permanent middle cerebral artery occlusion, reduce the morphological changes of nerve cells, decrease the expression of TNF-α,IL-1β and IL-6 in rat serum, increase the activity of SOD and CAT,and reduce the level of MDA.Furthermore, the expression levels of Notch l, Jagged l, Hes l and Bcl-2 mRNA were significantly increased, and the expression level of caspase-3 protein was decreased.Meanwhile, the number of VEGF and CD34 positive cells increased in the treatment group.The differences were statistically significant. Ershiwuwei Zhenzhu Pills has a protective effect on ischemic stroke rats, and its mechanism may be related to anti-inflammation, anti-oxidation, promotion of nerve cell proliferation, inhibition nerve cell apoptosis and promotion of angiogenesis.

Protective effect of extract of the Camellia japonica L. on cerebral ischemia-reperfusion injury in rats / Efeito protetor do extrato da Camellia japonica L. na lesão de reperfusão isquêmica cerebral em ratos

ABSTRACT Objective: We investigated the protective effect of the extract of the Camellia japonica L. flower on cerebral ischemia-reperfusion injury in rats. Methods: The rat ischemia-reperfusion injury was induced by middle cerebral artery occlusion for 90 minutes and reperfusion for 48 hours. The animals received an intravenous injection once a day of 20, 40, 80 mg/kg extract of C. japonica for three consecutive days before the ischemia reperfusion. The learning and memory function, the infarct volume, serum malondialdehyde (MDA) level and lactate dehydrogenase activity, and extravasation of immunoglobulin G (IgG) into cerebral parenchyma were assessed as the cell damage index. Results: Pretreatment with extract of C. japonica markedly reduced the infarct volume, serum malondialdehyde level and lactate dehydrogenase activity, and markedly inhibited the extravasation of IgG. Moreover, pretreatment with extract of C. japonica may also inhibit the learning and memory deficits induced by an ischemia-reperfusion injury. Conclusion: It was concluded that pretreatment with extract of C. japonica has a protective effect on cerebral ischemia-reperfusion injury in rats.

RESUMO Objetivo: Investigamos o efeito protetor do extrato da flor de Camellia japonica L. (ECJ) na lesão de reperfusão isquêmica cerebral (I/R) em ratos. Métodos: A lesão de I/R de rato foi induzida por uma oclusão da artéria cerebral média por 90 minutos e reperfusão por 48 horas. Os animais receberam uma injeção intravenosa uma vez ao dia de 20, 40, 80 mg/kg de ECJ por três dias consecutivos antes da I/R. A função de aprendizagem e memória, o volume do infarto, o nível sérico de malondialdeído (MDA), a atividade da desidrogenase láctica e o extravasamento de imunoglobulina (IgG) no parênquima cerebral foram avaliados como índices de dano celular. Resultados: O pré-tratamento com ECJ reduziu acentuadamente o volume do infarto, o nível sérico de MDA e a atividade da desidrogenase láctica, e inibiu marcadamente o extravasamento de IgG. Além disso, o pré-tratamento com ECJ também poderia inibir os déficits de aprendizado e memória induzidos pela lesão de I/R. Conclusão: O pré-tratamento com ECJ tem um efeito protetor contra lesão cerebral de I/R em ratos.

Comparação do efeito da nimodipina e da papaverina como vasodilatadores sobre o fluxo na artéria torácica interna esquerda / Comparison of the effects on the flow in the left internal thoracic artery using nimodipine and papaverine as vasodilators

OBJETIVO: O objetivo do presente estudo é comparar o fluxo da artéria torácica interna esquerda sob o efeito local farmacológico por embebição e o efeito intraluminal de bloqueador do canal de cálcio com um grupo controle com papaverina. MÉTODO: Foi realizado estudo prospectivo de 73 pacientes submetidos a revascularização do miocárdio, no período de quatro meses, nos quais se utilizou a artéria torácica interna esquerda como parte do grupo de enxertos, operados no período de julho de 2004 e novembro de 2004, para análise de fluxo comparativo entre dois fármacos. Os pacientes foram aleatorizados para receberem os vasodilatadores nimodipina ou papaverina. Foram determinados dois fluxos: o fluxo no Tempo 1, o qual representou o período de ação farmacológica por embebição (extraluminal), e o fluxo no Tempo 2, este representou a ação farmacológica intraluminal. A comparação das médias de fluxo entre os dois grupos de fármacos foi realizada através do teste não paramétrico de Mann-Whitney. RESULTADOS: Não há evidências de que os fluxos médios dos dois fármacos sejam diferentes no Tempo 1 (p=0,534). Os fluxos médios dos dois fármacos são semelhantes no Tempo 2 (p=0,063). CONCLUSÃO: Não há evidências de que os fluxos médios dos dois fármacos sejam diferentes sob ação por embebição (extraluminal), assim como os fluxos médios dos dois fármacos são semelhantes quando por ação farmacológica intraluminal, tornando a nimodipina uma opção como vasodilatador de ação local comparável à papaverina.

OBJECTIVE: To compare the flow of the left internal thoracic artery under a local pharmacological effect caused by the topical action on the arterial pedicle and the intraluminal effect of a calcium channel blocker with a control group using papaverine. METHODS: Over a period from July to November 2004, a prospective study was performed involving 73 patients who were submitted to coronary artery bypass surgery utilizing the left internal thoracic artery as one of a group of grafts. A comparative analysis of the flow was made when using two different pharmacological agents. The patients were randomized to receive either nimodipine or papaverine as vasodilators. Two types of flow were determined: the flow at Time 1 representing the period of topical action of the drug on the arterial pedicle (extraluminal) and the flow at Time 2 representing the intraluminal action of the drug. A comparison of the means of the two types of flow between the two groups of pharmacological agents was carried out using the non-parametric Mann-Whitney test. RESULTS: There is no evidence that the mean flow using the two pharmacological agents is different at Time 1 (p = 0.534) or at Time 2 (p = 0.063). CONCLUSIONS: There is no evidence that the mean flow varies due to the topical action of one or other drug or that the mean flow is different due to the intraluminal action, proving that nimodipine as a locally acting vasodilator is similar to papaverine.

Anti-seizure efficacy of nimodipine in pentylenetetrazole and kainic acid combined seizure models in mice.

The present study aimed at establishing two models of experimental seizures by combination treatment with subconvulsive doses of PTZ and kainic acid in adult male mice and evaluating the modulatory role of cerebroselective dihydropyridine calcium channel blocker, nimodipine. The CD50 +/- SEM value for PTZ was found to be 20.00 +/- 0.92 mg/kg, ip in kainic acid (administered at per se subconvulsive dose of 1.00 mg/kg, ip) pretreated mice while CD50 +/- SEM value for kainic acid was found to be 0.30 +/- 0.08 mg/kg, ip in PTZ (administered at per se subconvulsive dose of 30.00 mg/kg, ip) pretreated mice. Nimodipine (5.00 mg/kg, ip) significantly protected the mice from seizure in both of the combination in vivo seizure models. The results suggested synergistic interaction between PTZ and kainic acid at subconvulsive dose combination while the protective efficacy of nimodipine suggested the role of calcium ion as an important mediator for the genesis of seizures.

Pharmacologcal interactions between nimodipine; a calcium channel blocker, and some opioids; morphine and tramadol

This study was designed to evaluate the effect of the calcium channel blocker [CCB] nimodipine "dihydropyridine type" on the antinoeiceptive action of morphine and tramadol and their adverse effects on isolated rabbit hearts. Mice [weight, 20-30 g] were assigned to receive intra peritoneal [IP] one dose of nimodipine, morphine, tramadol and saline and were tested for their effect on the response latency using 55.5°C hot plate. The combinations of nimodipine and other agents also were tested. Nimodipine [800 micro g/kg], morphine [1000 micro g/kg] and tramadol [1600 micro g/kg] yielded increase in thermal threshold. Combined administration of nimodipine with subanalgesic dose of morphine [600 micro g/kg] produced a potent synergy, while combined administration of nimodipine with subanalgesic dose of tramadol [1000 micro g/kg] produced synergistic effect approach that produced by analgesic dose of tramadol alone. Isolated rabbit heart preparations were used to demonstrate the effects of one dose of nimodipine, morphine, tramadol and mammaline ringer solution on myocardial contractility using a modified langendaroffs apparatus. The combinations of nimodipine and other agents also were tested Nimodipine [0.25 micro g/ml], morphine [200 micro g/ml] yielded reduction in rabbit heart contraction, while tramadol [64 micro g/ml] did not yield significant reduction. Combined administration of nimodipine with subclinical concentration of morphine [100 micro g/ml] produced reduction in rabbit heart contraction near to that produced by analgesic dose of morphine alone, while combined administration of nimodipine with subclinical concentration of tramadol [32 micro g/ml] produced reduction in rabbit heart contraction near to that produced by nimodipine alone. This study showed that, CCBs and opioids produced synergistic antinocicepflve effect in response to acute thermal stimulus in animals. Co-administration of nimodipine and subclinical concentration of morphine decreased the detrimental negative inotropic effect of both drugs. These results suggest an important direction for development of acute pain strategies may focus on the voltage-dependent calcium channels in different afferent fibers

Effect of nimodipine, a dihydropyridine calcium channel antagonist on the pharmacokinetics of carbamazepine in rhesus monkeys.

Calcium channel antagonists have been shown to have an anticonvulsant activity in a variety of seizure models and also to potentiate the anticonvulsant activity of other standard antiepileptic drugs like carbamazepine, phenytoin and valporoate. A pharmacokinetic interaction may be involved in such potentiation. This cross over single dose study was carried out to find out if there was a pharmacokinetic interaction between carbamazepine, a commonly used antiepileptic drug and nimodipine, a dihydropyridine calcium channel antagonist in rhesus moneys. Carbamazepine 46 mg/kg and nimodipine 9.6 mg/kg was administered through a nasogastric tube and blood samples were collected at 0.5, 1, 2, 3, 6, 9, 12, 24, 48, 72 and 96 hours after drug administration and were assayed for carbamazepine. Nimodipine caused a significant increase in peak plasma concentration (C(max)) of carbamazepine and a decrease in plasma absorption half life (t1/2 alpha). There was no significant change in other pharmacokinetic parameters between the two groups. The results of the study suggest that concurrent administration of carbamazepine and nimodipine may cause a significant rise in carbamazepine concentration as may contribute to a potentiation of anticonvulsant effect of carbamazepine and an increase in the incidence of adverse effects warranting that nimodipine should be prescribed cautiously in epileptic patients receiving carbamazepine and it might be very appropriate to do therapeutic drug monitoring of carbamazepine in such patients.

Potentiation of analgesia and reversal of tolerance to morphine by calcium channel blockers.

Effect of four calcium channel blockers (CCBs) belonging to different chemical classes, alone and in combination with morphine was investigated on two models of pain sensitivity, i.e. formalin and tail flick tests in mice. All the studied CCBs, i.e. diltiazem, flunarizine, nimodipine and verapamil inhibited formalin-induced pain responses; however, with verapamil, though there was a trend towards a reduction of paw-licking response to formalin, it was not found to be statistically significant. In contrast, none of the CCBs affected the tail flick latency at any of the doses studied. Morphine, a mu-receptor agonist exerted a significant analgesic effect in formalin as well in tail flick tests. Pretreatment with all CCBs significantly enhanced the analgesic effect of morphine in both tests of nociception. Further, concomitant administration of one of the CCBs, diltiazem with morphine prevented the development of tolerance to the latter. However, combination of diltiazem with morphine, like morphine alone was found to be ineffective in morphine tolerant animals. Results, thus, show that CCBs produced an analgesic effect of their own in formalin-induced tonic pain and potentiated the analgesic activity of morphine. They also modulated opioid-induced tolerance.

Effects of garlic and nimodipine on cerebral blood flow and their neuroprotective effects after brain ischemia in rabbit

Nimodipine has been shown to have a neuroprotective effect. Garlic also displays features that are potentially effective in inhibiting ischemic damage. In this study the efficacy of both garlic and nimodipine in preventing ischemic brain injury were assessed. Twenty-four rabbits were divided into four groups: nimodipine-treated group [NP], garlic-treated group [GR], normal saline group [NS], and polyethylene glycol-treated as the vehicle group [VH]. All animals were subjected to 15 minutes of bilateral common carotid artery [CCA] occlusion. NP and GR groups received garlic and nimodipine 60 minutes before occlusion of the CCA respectively. Cerebral blood flow [CBF] was measured by Laser Doppler flowmetry, during and after the occlusion. Histopathology of the brain was blindly evaluated. The percentage of degenerated cells in the hippocampus was estimated and vascular congestion was graded on a 3-point scale [0, I, II]. After reperfusion, nimodipine and garlic increased the cerebral blood flow [CBF] by 41% and 24% respectively. Comparing these values to the extent of CBF increase in the VH and NS [2% in both] groups, the differences were statistically significant [p<0.05]. The percentage of degenerated neuronal cells in zone CA1 was 23%, 31%, 43% and 44% in NP, GR, VH and NS groups, respectively. NP and GR showed a higher grade of congestion compared to control groups [VH and NS][p<0.05]. This study demonstrates that neuronal damage to the rabbit hippocampus is reduced by garlic administration, although nimodipine can increase CBF more effectively

Effect of nimodipine on male reproductive functions in rats.

Nimodipine, a dihydropyridine calcium channel blocker, was administered orally using two different doses (40 mg and 60 mg/kg/day) to rats. Both short term (2 weeks) and long term (6 weeks) effects of the drug were observed. The drug administration resulted in a marked decrease in sperm density, sperm motility and acrozomal reaction. Zona-pellucida penetration by the sperm obtained from drug-treated animals was significantly lower when compared with sperm from normal animals. Nimodipine stimulated Ca2+ ATPase activity in isolated plasma membrane of rate spermatozoa. In conclusion, short term and long term administration of nimodipine has deleterious effect on male reproductive functions in rats.

Effects of intrathecal L-and N-type calcium channel blockers on the antinociception evoked by opioid agonists in the rat tail flick test

The effects of intrathecal administration of nimodipine or omega-conotoxin GVIA(L- and N-type calcium channel blockers, respectively) alone or followed by DAMGO, DADLE or bremazocine (mu-, delta- and kappa- opioid agonists, respectively) were studied on the rat tail flick test. The N- (16 to 64 pmoles), but not the L-type blocker (60 to 240 pmoles) produced a dose and time-dependent increase in the latency for the tail-flick reflex. DAMGO (30 to 120 pmoles) or bremazocine (190 to 560 pmoles), but not DADLE (50 to 200 pmoles), produced a dose-dependent increase in the latency for the tail-flick reflex. The effect of the highest dose of DAMGO was smaller, while the effects of DADLE and bremazocine were not changed after nimodipine (60 pmoles). The effects of DADLE were significantly potentiated, while the effects of DAMGO and bremazocine were not changed after omega-conotoxin GVIA (16 pmoles). The intrathecal administration of an N-type calcium channel blocker with a delta-opioid agonist seems to be the most effective combination to produce antinociception in the rat tail flick test.

Doença de Alzheimer: tratamento farmacológico / Alzeheimer's disease: pharmacological treatment

O tratamento farmacológico da doença de Alzheimer é considerado tomando como base os fatores etiológicos/fisiopatológicos subjacentes ao processo neurodegenerativo. Assim, é dado enfoque aos estudos terapêuticos pré-clínicos em relaçäo aos distúrbios básicos (genéticos, apoptose, placas senis, amaranhados neurofibrilares). O tratamento compensatório com utilizaçäo de estratégias colinérgicas (dando-se destaque ao uso de drogas inibidoras da acetilcolinesterase) e também relacionadas com outros neurotransmissores é analisado, assim como a terapêutica em funçäo de outros aspectos fisiopatológicos (neuroprotetores, antioxidantes, antiinflamatórios, metabólicos, tóxicos). Finalmente säo considerados os aspectos gerais do tratamento dos transtornos de comportamento/psicógicos que acompanham a doença

Effect of nitrendipine, nimodipine and nisoldipine on water and electrolytes excretion in rats.

In water loaded (5 ml/100 g) unanesthetized rats. nitrendipine (NT), nimodipine (NM) and nisoldipine (NS) (5 mg/ kg, i.p.) caused significant (P < 0.01) increase in water and Na+ excretion. However, there was no significant increase in K+ excretion after NT, NM and NS administration. NS was more potent in increasing excretion of water load as compared to NT and NM. The glomerular filtration rate as assessed by creatinine clearance, was significantly (P < 0.01) increased in NT, NM and NS (5 mg/kg, i.p.) treated groups as compared to control. The mean creatinine clearance values after NT, NM and NS were 26.95 +/- 0.35, 22.11 +/- 0.72 and 28.13 +/- 0.95 respectively as compared to 22.19 +/- 0.51, 18.77 +/- 0.42 and 22.97 +/- 0.60 in corresponding control groups. The results of the study suggest that in addition to other effects, NT, NM and NS have a selective inhibitory effect on Na+ handling mechanisms in the nephron.

Effect of nitrendipine, nimodipine and nisoldipine on experimentally induced myocardial infarction in rats.

Cardiac necrosis was produced in rats by administering isoproterenol sulphate (85 mg/kg, sc for 4 days). The myocardial damage was proved by observing the elevated levels of serum aspartate aminotransferase, ++alanine aminotransferase and lactate dehydrogenase and the changes were confirmed by his topathology. Nitrendipine, nimodipine and nisoldipine (10 mg/kg, ip) significantly reduced the elevated levels of these enzymes. The average degree of cardiac necrosis in these rats when observed microscopically and histologically was also found to be significantly reduced on pretreatment with these drugs. Nisoldipine was more effective in preventing cardiac necrosis as compared to nitrendipine and nimodipine.

Effect of chemically different calcium antagonists on lipid profile in rats fed on a high fat diet.

Different classes of calcium antagonists, viz. verapamil (diphenylalkylamine), diltiazem (benzothiazepine), nifedipine, felodipine and nimodipine (dihydropyridines), were examined for their effects on lipid profile in rats. Clofibrate was the reference standard. Clofibrate significantly prevented the rise of serum triglycerides and total cholesterol produced by high fat diet and raised antiatherogenic index to 1.6 times than that of high fat diet controls. Of the calcium antagonists studied, felodipine was most effective in preventing the rise of serum triglycerides and total cholesterol in high fat diet fed rats. Felodipine's antiatherogenic index was very high (886%)--much more than that of clofibrate (303%). Diltiazem and nimodipine which also significantly prevented the rise in triglycerides and total cholesterol produced by high fat diet had a moderately beneficial antiatherogenic index similar to that of clofibrate. Though verapamil and nifedipine slightly increased the triglyceride levels, total cholesterol levels were reduced only by verapamil and not by nifedipine. Despite this both these drugs moderately raised antiatherogenic index similar to clofibrate.

Acción de la nimodipina en el déficit isquémico retardado de la hemorragia subaracnoidea / Effect of nimodipine in the delayed ischemic deficit of subarachnoid hemorrhage

Se incluyen 35 pacientes de ambos sexos, ingresados al Servicio de neurocirugía del Hospital C. Van Buren entre noviembre 1986 a julio 1988. Los criterios de inclusión al estudio fueron edad entre los 15 y 70 años, diagnóstico de hemorragia subaracnoidea (H.S.A.) secundaria a aneurisma cerebral roto, ingresados dentro de las 96 horas posteriores a la H.S.A. inicial y con grado neurológico según la escala de Hunt y Hess de I a V. El tratamiento consistió en nimodipina (Nimotop-Bayer) EV 2 mg/hr, durante 14 días, y luego 60 mg c/ 6 hrs. oral durante 7 días. En esta comunicación interesa comentar 4 aspectos: 1) presencia de complicaciones neurológicas más frecuentes durante las primeras 2 semanas de evolución de la H.S.A.: resangriamiento, 0 casos, déficit isquémico retardado (DIR) 9 casos (25,7%) ya sea DIR temporal, 5 casos o DIR permanente, 4 casos. Se comenta que de los 5 casos con DIR temporal a 4 se efectuó clipaje temporal de arterias aferentes durante el acto operatorio, y que de los 4 con DIR permanente a 2 se le efectuó clipaje temporal por ruptura prematura del aneurisma (5,7%), en 1 caso el clip definitivo incluyó una arteria perforante, y 1 caso demostró en la T.A.C. de control un pequeño infarto frontal probablemente debido a presión de la espátula. 2) Clínicamente la nimodipina EV demostró ser efectiva al mejorar tanto el grado de compromiso neurológico (según Hunt y Hess), como el grado de compromiso de conciencia (según escala de Glasgow), pudiendo optar así con mejores posibilidades a la cirugía. 3) En esta serie 11 casos presentaron vasoespasmo angiográfico (31,4%), 5 casos durante el tratamiento (14,2%) y 6 antes de iniciar el tratamiento con nimodipina (17,2%)...